Hydroxy- and alkoxycarbonylation of unsaturated compounds such as alkenes and alkynes (also referred to in the art as hydrocarbonylation and hydroesterification respectively) are very useful reactions in synthetic chemistry. They can deliver carboxylic acid derivatives (acids, esters) in one step with essentially no waste products. Consequentially these reactions are often used in the production of bulk chemicals and fine chemicals, and potentially useful in the synthesis of pharmaceutically active compounds.
I del Rio et al. (J. Mol. Catal. A-Chem., 2000, 161, 39-48), in a report into the palladium-catalysed hydroxycarbonylation of styrene, compared the effect of monodentate phosphine and bidentate diphosphine ligands. Whilst bidentate diphosphine ligands are reported as having certain advantages, this publication also describes how hydroxycarbonylations require significantly more forcing conditions when diphosphines are used as ligands, with typical temperatures of around 150° C. J J R Frew et al. (Dalton Trans., 2008, 1976) also describe examples of hydroxycarbonylation of styrene in which certain diphosphines allow good yields at lower temperatures (ca. 100° C.) to be achieved. In these reports, monomeric palladium catalysts are described—in which a single palladium centre is chelated by the phosphorus atoms in the diphosphine—or catalysts formed in situ from an excess of diphosphine ligand relative to palladium under conditions in which the stoichiometry of reactants means that the formation of monomeric palladium catalysts may be expected.
The use of dimeric catalysts in methoxycarbonylation or hydroxycarbonylation reactions has never been reported. An industrial process for methoxycarbonylation of the simple alkene, ethylene displays high reactivity (see W Clegg et al., Chem. Commun., 1999, 1877). Catalysts are formed in situ, and both monomeric salts of type [Pd(P^P)dba] and Pd(P^P)Cl2 (in which P^P represents a diphosphine) are used along with a tetrameric palladium compound was also isolated in mechanistic studies on these specific diphosphine ligands.
As is well known, it is of often of particular benefit to be able to produce more of one stereoisomer than another, in particular an optical isomer substantially free of its stereoisomers, where a target compound exhibits stereoisomerism. This benefit applies to hydrocarbonylation and hydroesterification reactions as much as any other reactions.
Classical methods of achieving differential amounts of stereoisomers have typically involved the separation of the stereoisomers, e.g. optically active isomers, from stereoisomeric, e.g. optically inactive (racemic), mixtures. However, such resolutions are often laborious, expensive and generate waste products. Owing to these difficulties, asymmetric synthetic methods have been developed in which optically active catalysts are used to carry out reactions in which an excess of one stereoisomer is produced.
Effective processes for the carbonylation of unsaturated compounds, and, which produce an excess of one optical isomer, are a key technology for the more efficient production of optically active carboxylic acids and esters. However, there is a continuing need for catalysts useful in such reactions that have good reactivity, stability and chemoselectivity.
Various hydroxycarbonylations and alkoxycarbonylations giving optically inactive products have been described. A. Seayad et al. (Org. Lett., 1999, 1, 459-462) describe the hydroxycarbonylation of alkenes using palladium complexes of the triphenylphosphine in combination with lithium chloride and p-toluenesulfonic acid, typically used at 20 mol % relative to the alkene reactant. These processes were shown to afford good yields of optically inactive carboxylic acids at temperatures of around 115° C. Methoxycarbonylation of alkenes is generally understood to proceed under milder conditions than the analogous hydroxycarbonylation. H Ooka et al. (Chem. Commun., 2005, 1173-1175) describe that Pd(OAc)2 in combination with certain diphosphines combined in excess amounts relative to palladium can promote methoxycarbonylation of styrene at room temperature. C Godard et al. (Helvetica Chim. Acta, 2006, 89, 1610-1622) describe that temperatures of 100° C. are sufficient to achieve significant yields in methoxycarbonylation of styrene, although 150° C. was preferred. Although hydroxycarbonylation of styrene using diphosphines has never given high ratios of optical isomers (see I del Rio et al., infra), C Godard et al. describe ratios of the product esters of up to 92:8. E Guiu et al. (Organometallics, 2006, 25, 3102-3104) describe good yields in the same reaction at 90° C. although the ratio of optical isomers are not described as exceeding 70:30.
There are many examples in the art in which optionally optically active diphosphines chelated to single metal ions are used in various processes of asymmetric catalysis. However, there are very few reports that describe the asymmetric hydroxycarbonylation of alkenes. I del Rio et al, (Eur. J. Inorg. Chem., 2001, 2001(11), 2719-2738) and H Alper & N Hamel (J. Am. Chem. Soc., 1990, 112(7), 2803-2804) report high ratios of optical isomers upon the asymmetric hydroxycarbonylation of alkenes using catalysts formed from a simple palladium salt and a chiral phosphoric acid. Nevertheless, 10-20 mol % of the Pd catalyst is used, suggesting a low reactivity.
I del Rio et al. (infra) describe that moderate yields of modestly optically enriched carboxylic acids can be realised at 150° C. using optically active diphosphine ligands. However, the ratio of the optical isomers does not exceed 56:44 (an enantiomeric excess of 12%). The diphosphine palladium-containing catalysts comprise either isolated monomeric complexes of formula [Pd(P^P)X2] (P^P is diphosphine; X is a halide), or are formed in situ with a palladium salt.
The processes described above bring useful technical knowledge, gradual improvement in performance and understanding, and include technology developed for two very specific applications: (methoxycarbonylation of ethylene and hydrocarbonylation of vinyl napthalenes in a racemic sense; methoxycarbonylation of ethylene does not require control over selectivity owing to the symmetry of ethylene, and the hydrocarbonylation of vinyl napthalenes in a racemic sense does not seek stereoselective control. However, there is an ongoing need for catalytic methods and catalysts more generally useful in the carbonylation of unsaturated compounds, and in particular in the hydroxycarbonylation, alkoxycarbonylation, aryloxycarbonylation or thiocarbonylation, e.g. hydroxycarbonylation and alkoxycarbonylation, of unsaturated compounds, that can preferably afford high stereospecificities in asymmetric reactions and/or with good yields of product. The present invention addresses this need in the art.